The sympathetic branch of the autonomic system is a key regulator of blood pressure. Secretory vesicles of chromaffin cells and sympathetic axons release co-stored transmitters by exocytosis into the bloodstream or synaptic clefts, where they contact cardiovascular target cells. In addition to catecholamines, the secretory "quantum" includes neuropeptides (such as NPY), and -chromogranins, precursors of active peptides which influence vascular responses to sympatho- adrenal activation, and hence blood pressure. This Program links 4 projects with longstanding collaborations in synthesis, release, and actions (pre- and post-synaptic) of these transmitters, integrating their effects on blood pressure. Central hypotheses and themes focus interactive efforts. Projects 1 & 2 include human studies, and Project 2 probes sympathetic neuroeffector mechanisms in intact rodents, while Projects 2-4 clarify cellular mechanisms in transmitter biosynthesis and release, and also exploit ex vivo biological materials from Projects 1 & 2 for phenotyping. Human studies probe the genetic basis of heritable alterations in autonomic activity in pedigrees with hypertension (Project 1; Core D), and each Project (1-4) participates in phenotyping unique autonomic traits in pedigree members. Already, significant, novel genetic linkages have emerged, with intriguing allelic variations found in the alpha1beta-adrenergic receptor and the renal kallikrein promoter. Five core facilities provide defined cell populations, signal probes, genotyping, physical mapping, informatics, catecholamine and vasoactive peptide assays, and imaging. Using molecular biologic and informatic tools, the program aims to achieve a new level of understanding of the dynamic complexity of the sympathetic neuroeffector junction, and how its components contribute to heritable changes in blood pressure, and ultimately to human hypertension. This program therefore represents a unique opportunity to define the genetic basis of autonomic dysfunction in human essential hypertension.